Introduction

Blood develops initially within the core of "blood islands" in the mesoderm both within the embryo (mesoderm) and outside the mesoderm (extra-embryonic mesoderm). There then follows a series of "relocations" of the stem cells to different organs (liver, spleen and thymus) within the embryo and fetus. In the adult, these stem cells are located in the bone marrow. At the time when blood first forms there are no bones, and it is only with bone development that we see bone marrow formation and relocation of blood stem cells.

The clavicle is the first fetal bone to contain marrow.[1] Granulocyte-colony stimulating factor (G-CSF) may initiate neutrophil production, with neutrophils first appearing in the clavicle marrow at 10 - 11 weeks.[2] The fetal white blood cells (neutrophils, monocytes, and macrophages) develop, though mononuclear phagocytes do not mature until after birth.

Blood initially develops along with the blood vessels in which it will flow. Blood itself is considered as a form of "liquid conective tissue" consisting of a fluid and cellular component.

Stem cells that form blood cells (Hematopoietic Stem Cells, HSCs) change their location during development moving from tissue to tissue until their adult bone marrow location is formed and populated.

Angioblasts initially form small cell clusters (blood islands) within the embryonic and extraembryonic mesoderm. These blood islands extend and fuse together making a primordial vascular network. Within these islands 2 populations of cells exist: peripheral and core. The peripheral cells form endothelial cells while the core cells form blood cells (haemocytoblasts).

Some Recent Findings

Adult Erythrocyte, Thrombocyte and Lymphocyte

Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1[3] Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs." Stem Cells

Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans[4] "Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development. We also provide evidence that the fetal T cell lineage is biased toward immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth."

Runx1 is required for the endothelial to haematopoietic cell transition[5] "It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters and that Runx1 functions during the transition from 'haemogenic endothelium' to Haematopoietic stem cells (HSCs). ...Collectively these data show that Runx1 function is essential in endothelial cells for haematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed." (More? OMIM - Runt-Related Transcription Factor 1 - Runx1 )

Discordant developmental waves of angioblasts and hemangioblasts in the early gastrulating mouse embryo[6] "An in vitro model of vasculogenesis and hematopoiesis in mouse has been used to identify a separate developmental pathway in which the angioblast lineage forms from mesoderm prior to and independent of hemangioblast development. This result differs from our current understanding where hemangioblasts are considered the common progenitors of cells in vessels and in blood."

More recent papers

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Blood Stem Cells

Hematopoietic stem cell location (mouse)

Hematopoietic and stromal cell differentiation

A recent study in embryonic mouse development mapped the location of Hematopoietic stem cells (HSCs) during development. In the adult, blood cell formation is restricted to bone marrow, where a population of blood "stem cells" reside and differentiate into both red and white blood cells.

Hematopoietic stem cells (HSCs) origins have been the source of some recent controversy, as to yolk sac and dorsal aorta contributions.

[5] "It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters and that Runx1 functions during the transition from 'haemogenic endothelium' to Haematopoietic stem cells (HSCs). ...Collectively these data show that Runx1 function is essential in endothelial cells for haematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed."

[7] "Hematopoietic system involves sequential transfers of hematopoietic stem cells (HSCs) generated in the yolk sac blood islands, to successive hematopoietic organs as these become active in the embryo (fetal liver, thymus, spleen and eventually bone marrow). 4.5 day gap between appearance of the yolk sac blood islands and the stage of a fully active fetal liver. Avian studies identified yolk sac produce only erythro-myeloid precursors that become extinct after emergence of a second wave of intra-embryonic HSCs from the region neighbouring the dorsal aorta." (text modified from paper abstract)

[8] "In the 1960s a series of ontogenetic studies in birds and subsequently in mice revealed that hematopoietic and lymphoid development involved migration streams of primitive cells that colonized developing primary lymphoid organs as well as spleen, marrow, and liver. The yolk sac was proposed as the ultimate origin of these lympho-hematopoietic precursors. Subsequent studies identified a region associated with the dorsal aorta as the primary site of "definitive" stem cells. These opposing views are currently achieving a compromise that recognizes that both sites contribute stem cells involved in seeding the developing tissues." (text from abstract)

Fetal Blood Facts

Fetal Blood

Fetal red blood cells (rbc) can also be identified by the presence of a nucleus that is absent in the adult red blood cell. Fetal red blood cells also contain a fetal haemoglobin which has different oxygen/carbon dioxide binding characteristics to adult red blood cell haemoglobin.

Maternal and fetal blood never mix, with exchange occuring across a number of membranes found in the placenta. (More? see Placenta Development)

Adult Blood Cell Differentiation

Red Blood Cells

Fetal red blood cells

Red blood cells (rbc) are the transporters of oxygen and carbon dixide in the blood.

When blood is centrifuged, the total % amount is known as the haemocrit. A low haemocrit or haemoglobin level leads to anemia. Adult red blood cells contain no nucleus and have a limited lifespan. The lower oxygen tension at high altitudes leads to the body producing more rbc to compensate.

Most fetal red blood cells retain their nucleus, while adult red blood cells undergo enucleation as part of normal reticulocyte maturation within bone marrow before being released into circulation.

Blood Progenitor Development

In the mouse, the yolk sac has an early important role in the provision of progeitor cells; before E8.0 all progenitors are found in the yolk sac, which remains enriched compared with the embryo from E9.5 to E10.5. (More? Mouse Development)

Non-Granulocytes

Lymphocytes

Platelets

140 - 440 x 109/l

not a cell, a cell fragment.

Altitude

The lower oxygen tension at high altitudes leads to the body producing more rbc to compensate. This means that people living at high altitudes have a higher haemocrit and/or haemoglobin level. This is also the reason why atheletes train at high altitude, to give them a higher gas carrying level when they return to sea level. This altitude effect on returning to sea level is gradually lost.

Alternately, this is also the basis of "altitude sickness" when people move rapidly from sea level to high altitude regions and their body has not yet been able to compensate.

Fetal

Proportions of the combined ventricular output in the major vessels of the human fetal circulation by phase contrast MRI. Mean flows (8 subjects) in the major vessels of the human fetal circulation by phase contrast MRI (median gestational age 37 weeks, age range of 30–39 weeks).[13]

AAo - Ascending aorta

MPA - main pulmonary artery

DA - ductus arteriosus

PBF - pulmonary blood flow

DAo - descending aorta

UA - umbilical artery

UV - umbilical vein

IVC - inferior vena cava

SVC - superior vena cava

RA - right atrium

FO - foramen ovale

LA - left atrium

RV - right ventricle

LV - left ventricle

Angiogenesis

blood vessel formation

vasculogenesis

also occurs in adult and disease

begins week 3 in extraembryonic mesoderm

yolk sac

connecting stalk

chorion

Growth Factors - Vascular endothelial growth factor (VEGF), PIGF

angioblasts form clusters - blood islands

blood islands extend and fuse together forms a network

2 populations of cells

peripheral- form endothelial cells

core- form blood cells (haemocytoblasts)

all vessels (arteries and veins) appear initially the same

Blood formation

blood formation occurs later (week 5)

occurs throughout embryoic mesenchyme

liver

then spleen, bone marrow, lymph nodes

Maternal Blood

During pregnancy, maternal blood volume increases by about 50% and the uterine blood flow increases 10 to 12 fold. Uterine flow increase is due mainly to the trophoblast cell invasion of the spiral arteries opening them into blood-filled spaces of the placenta.

There are also changes in circulating glucose due to increases in insulin resistance during pregnancy.

Non-Granulocytes

Lymphocytes

Platelets

140 - 440 x 109/l

not a cell, a cell fragment.

Abnormalities

Haemolytic Disease of the Newborn

Haemolytic Disease of the Newborn (fetal erythroblastosis) is an immune problem arising from fetus Rh+ /maternal Rh-. Leakage of blood from fetus leads to maternal anti-Rh antibodies, which can then be dangerous for future pregnancies. This has in the past been identified by blood typing fetal blood by invasive prenatal diagnostic techniques or postnatally from the neonate. A recent study has shown that Non-Invasive Prenatal Testing (NIPT) can be used to identify presence or absence of the RhD type from circulating fetal DNA in the maternal blood after about 11 weeks gestation.[15]

Rhesus factor D (RhD)

RhD polypeptide is an integral membrane protein expressed on erythrocytes.

Sickle Cell Anemia

People who have this form of sickle cell disease inherit two sickle cell genes (“S”), one from each parent. This is commonly called “sickle cell anemia”, and is usually the most severe form of the disease. The name comes from the "sickle" shape of the RBC compared to the normal "donut" shape.

The scanning electron micrograph (SEM) on the right shows the ultrastructural morphology of a sickle cell RBC found in a blood specimen of an 18 year old female patient with sickle cell anemia, (HbSS).

Sickle cell RBC (Image CDC)

Thalassemia

Thalassemia is a group of inherited (genetic) blood disorders most frequently in people of Italian, Greek, Middle Eastern, Southern Asian and African Ancestry. The most severe form of alpha thalassemia, affecting mainly people of Southeast Asian, Chinese and Filipino ancestry, results in fetal or newborn death.

The two main types of thalassemia are called "alpha" and "beta," depending on which part of an oxygen-carrying protein in the red blood cells is lacking. Both types of thalassemia are inherited in the same manner. A child who inherits one mutated gene is a carrier, which is sometimes called "thalassemia trait." Most carriers lead completely normal, healthy lives.

growth factor - usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg VEGF, shh)

pericardium - covers the heart. Formed by 3 layers consisting of a fibrous pericardium and a double layered serous pericardium (parietal layer and visceral epicardium layer).

pericytes - (Rouget cells) cells located at the abluminal surface of microvessels close to endothelial cells, mainly found associated with CNS vessels and involved in vessel formation, remodeling and stabilization.

pharyngeal arches (=branchial arches, Gk. gill) series of cranial folds that form most structures of the head and neck. Six arches form but only 4 form any structures. Each arch has a pouch, membrane and groove.

truncus arteriosus - an embryological heart outflow structure, that forms in early cardiac development and will later divides into the pulmonary artery and aorta. Term is also used clinically to describe the malformation where only one artery arises from the heart and forms the aorta and pulmonary artery.

vascular endothelial growth factor - (VEGF) A secreted protein growth factor family, which stimulates the proliferation of vasular endotheial cells and therefore blood vessel growth. VEGF's have several roles in embryonic development. The VEGF family has 7 members (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PlGF) that have a common VEGF homology domain. PIGF is the placental growth factor. They act through 3 VEGF tyrosine kinase membrane receptors (VEGFR-1 to 3) with seven immunoglobulin-like domains in the extracellular domain, a single transmembrane region, and an intracellular tyrosine kinase sequence.

vasculogenesis - the formation of new blood vessels from mesoderm forming the endothelium. Compared to angiogenesis that is the process of blood vessel formation from pre-existing vessels.

fetal drug addiction - occurs when drugs used maternally cross the placental barrier and can establish addiction in the unborn fetus.

growth factor - usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg VEGF, shh)

mesoderm - the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.

neural crest - cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Neural crest cells also contribute to major cardiac outflow vessels.

patent ductus arteriosus - (P.D.A.)

pharyngeal arches - (=branchial arches, Gk. gill) form structures of the head. Six arches form but only 4 form any structures. Each arch has a pouch, membrane and groove.

tetralogy of Fallot- Named after Etienne-Louis Arthur Fallot (1888) who described it as "la maladie blue". The syndrome consists of a number of a number of cardiac defects possibly stemming from abnormal neural crest migration.